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Cytokine-Inducible SH2-Containing Protein Suppresses PRL Signaling by Binding the PRL Receptor

Institut National de la Santé et la Recherche Médicale, Unité 344, Endocrinologie Moléculaire, Faculté de Médecine Necker (F.D., E.S., P.A.K., M.E.), 75730 Paris, France; and Laboratoire de Physiologie Générale et Comparée (F.D., B.D.), Muséum National d’Histoire Naturelle, Unité Mixte de Recherche 8572 Centre National de la Recherche Scientifique, 75231 Paris cedex 05, France

Address all correspondence and requests for reprints to: Marc Edery, Institut National de la Santé et la Recherche Médicale, Unité 344, Faculté de Médecine Necker Enfants malades, 156 rue de Vaugirard, 75730 Paris Cedex 15, France. E-mail: marc.edery{at}necker.fr

Inhibition of PRL hormone signaling by suppressor of cytokine signaling (SOCS)/cytokine-inducible SH2-containing protein (CIS) was investigated in transfected HEK 293 cells. We used the physiologically relevant wild-type ß-casein promoter as a target gene for PRL action. We demonstrate that CIS produces a 70% inhibition of PRL signaling by a mechanism distinct from, and downstream of, the effect of SOCS-1 on JAK2. This inhibition involves association with the PRL receptor (PRLR), resulting in the inhibition of signal transducer and activator of transcription 5 (STAT5) activation. Further, we show that SOCS-3 coimmunoprecipitates with the PRLR. These data suggest that SOCS-3 involves a second pathway for the inhibition of PRL signaling other than JAK2 inhibition. Additional results indicate that SOCS-2 can play a more important potentiator role on PRL signaling, resulting in a restoration of 50% of transcriptional inhibition induced by SOCS-3 and a restoration of 100% of transcriptional inhibition induced by CIS. SOCS-2 was able to block the inhibitory effect of SOCS-1. These results indicate that SOCS-2 seems to be an antagonist of the other SOCS. SOCS-1 binds JAK2 and inhibits its phosphorylation; SOCS-3 does not bind JAK2 but binds the PRLR that may mediate its inhibition of JAK2; and finally, CIS binds the PRLR but inhibits signal transducer and activator of transcription 5 rather than JAK2.

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